Ameliorative effect of GLP1 agonist on vascular calcification in normoglycemic aged rat aorta via miR34a/SIRT6/NRF2/HO-1 signalling pathway.

Abstract

Medial arterial calcification (MAC), an age related vascular histological alteration, accounts for cardiovascular mortality, where cellular senescence and disturbed redox haemostasis play a role. Liraglutide (LRGT), an approved anti-diabetic agent, recently showed vascular benefits. So, we examined the probable protective impact of LRGT against aging-induced MAC and in addition, the role of MiR-34a/SIRT6 pathway is delineated. Rats were classified into two groups; young (3-4 months old) and aged (24 months old n = 24). Eight rats from the aged group were sacrificed at the beginning of the experiment and the remaining rats completed the study with or without LRGT for 8 weeks. Administration of LRGT ameliorated medial calcification, as shown by Alizarin red staining and calcium content assay, and downregulated runt-related transcription factor 2 (RUNX2) and osteocalcin, while enhancing α-SMA immunoexpression and improving histological appearance in aged rats' aorta. Additionally, mitigation of aging-induced elevation of blood pressure (SBP and DBP), the senescent p53 and p16 proteins, and senescence-associated secretory phenotype including TNFα and IL-6 was also evident with LRGT. Moreover, LRGT treatment was associated with decline in MDA, 8-OHdG and Keap1 and increased GSH, NRF2, and its targeted antioxidants such as HO-1, NQO1, and GCLC. LRGT also enhanced eNOS immunoexpression in aged rats. At the molecular level, LRGT upregulated aortic SIRT6 mRNA epression and downregulated its upstream MiR-34a transcript level. We concluded that LRGT alleviated MAC during physiological aging mostly through MiR-34a/SIRT6-mediated repression of cellular senescence and repairing the Keap1/NRF2/antioxidants cascades.